The (bad) luck of the draw; more evidence

A while back, Vogelstein and Tomasetti (V-T) published a paper in Science in which it was argued that most cancers cannot be attributed to known environmental factors, but instead were due simply to the errors in DNA replication that occur throughout life when cells divide.  See our earlier 2-part series on this.

Essentially the argument is that knowledge of the approximate number of at-risk cell divisions per unit of age could account for the age-related pattern of increase in cancers of different organs, if one ignored some obviously environmental causes like smoking.  Cigarette smoke is a mutagen and if cancer is a mutagenic disease, as it certainly largely is, then that will account for the dose-related pattern of lung and oral cancers.

This got enraged responses from environmental epidemiologists whose careers are vested in the idea that if people would avoid carcinogens they'd reduce their cancer risk.  Of course, this is partly just the environmental epidemiologists' natural reaction to their ox being gored--threats to their grant largesse and so on.  But it is also true that environmental factors of various kinds, in addition to smoking, have been associated with cancer; some dietary components, viruses, sunlight, even diagnostic x-rays if done early and often enough, and other factors.

Most associated risks from agents like these are small, compared to smoking, but not zero and an at least legitimate objection to V-T's paper might be that the suggestion that environmental pollution, dietary excess, and so on don't matter when it comes to cancer is wrong.  I think V-T are saying no such thing.  Clearly some environmental exposures are mutagens and it would be a really hard-core reactionary to deny that mutations are unrelated to cancer.  Other external or lifestyle agents are mitogens; they stimulate cell division, and it would be silly not to think they could have a role in cancer.  If and when they do, it is not by causing mutations per se.  Instead mitogenic exposures in themselves just stimulate cell division, which is dangerous if the cell is already transformed into a cancer cell.  But it is also a way to increase cancer by just what V-T stress: the natural occurrence of mutations when cells divide.

There are a few who argue that cancer is due to transposable elements moving around and/or inserting into the genome where they can cause cells to misbehave, or other perhaps unknown factors such as of tissue organization, which can lead cells to 'misbehave', rather than mutations.

These alternatives are, currently, a rather minor cause of cancer.  In response to their critics, V-T have just published a new multi-national analysis that they suggest supports their theory.  They attempted to correct for the number of at-risk cells and so on, and found a convincing pattern that supports the intrinsic-mutation viewpoint.  They did this to rebut their critics.

This is at least in part an unnecessary food-fight.  When cells divide, DNA replication errors occur.  This seems well-documented (indeed, Vogelstein did some work years ago that showed evidence for somatic mutation--that is, DNA changes that are not inherited--and genomes of cancer cells compared to normal cells of the same individual.  Indeed, for decades this has been known in various levels of detail.  Of course, showing that this is causal rather than coincidental is a separate problem, because the fact of mutations occurring during cell division doesn't necessarily mean that the mutations are causal. However, for several cancers the repeated involvement of specific genes, and the demonstration of mutations in the same gene or genes in many different individuals, or of the same effect in experimental mice and so on, is persuasive evidence that mutational change is important in cancer.

The specifics of that importance are in a sense somewhat separate from the assertion that environmental epidemiologists are complaining about.  Unfortunately, to a great extent this is a silly debate. In essence, besides professional pride and careerism, the debate should not be about whether mutations are involved in cancer causation but whether specific environmental sources of mutation are identifiable and individually strong enough, as x-rays and tobacco smoke are, to be identified and avoided.  Smoking targets particular cells in the oral cavity and lungs.  But exposures that are more generic, but individually rare or not associated with a specific item like smoking, and can't be avoided, might raise the rate of somatic mutation generally.  Just having a body temperature may be one such factor, for example.

I would say that we are inevitably exposed to chemicals and so on that will potentially damage cells, mutation being one such effect.  V-T are substantially correct, from what the data look like, in saying that (in our words) namable, specific, and avoidable environmental mutations are not the major systematic, organ-targeting cause of cancer.  Vague and/or generic exposure to mutagens will lead to mutations more or less randomly among our cells (maybe, depending on the agent, differently depending on how deep in our bodies the cells are relative to the outside world or other means of exposure).  The more at-risk cells, the longer they're at risk, and so on, the greater the chance that some cell will experience a transforming set of changes.

Most of us probably inherit mutations in some of these genes from conception, and have to await other events to occur (whether these are mutational or of another nature as mentioned above).  The age patterns of cancers seem very convincingly to show that.  The real key factor here is the degree to which specific, identifiable, avoidable mutational agents can be identified.  It seems silly or, perhaps as likely, mere professional jealousy, to resist that idea.

These statements apply even if cancers are not all, or not entirely, due to mutational effects.  And, remember, not all of the mutations required to transform a cell need be of somatic origin.  Since cancer is mostly, and obviously, a multi-factor disease genetically (not a single mutation as a rule), we should not have our hackles raised if we find what seems obvious, that mutations are part of cell division, part of life.

There are curious things about cancer, such as our large body size but delayed onset ages relative to the occurrence of cancer in smaller, and younger animals like mice.  And different animals of different lifespans and body sizes, even different rodents, have different lifetime cancer risks (some may be the result of details of their inbreeding history or of inbreeding itself).  Mouse cancer rates increase with age and hence the number of at-risk cell divisions, but the overall risk at very young ages despite many fewer cell divisions (yet similar genome sizes) shows that even the spontaneous mutation idea of V-T has problems.  After all, elephants are huge and live very long lives; why don't they get cancer much earlier?

Overall, if if correct, V-T's view should not give too much comfort to our 'Precision' genomic medicine sloganeers, another aspect of budget protection, because the bad luck mutations are generally somatic, not germline, and hence not susceptible to Big Data epidemiology, genetic or otherwise, that depends on germ-line variation as the predictor.

Related to this are the numerous reports of changes in life expectancy among various segments of society and how they are changing based on behaviors, most recently, for example, the opiod epidemic among whites in depressed areas of the US.  Such environmental changes are not predictable specifically, not even in principle, and can't be built into genome-based Big Data, or the budget-promoting promises coming out of NIH about such 'precision'.  Even estimated lifetime cancer risks associated with mutations in clear-cut risk-affecting genes like BRCA1 mutations and breast cancer, vary greatly from population to population and study to study.  The V-T debate, and their obviously valid point, regardless of the details, is only part of the lifetime cancer risk story.

ADDENDUM 1
Just after posting this, I learned of a new story on this 'controversy' in The Atlantic.  It is really a silly debate, as noted in my original version.  It tacitly makes many different assumptions about whether this or that tinkering with our lifestyles will add to or reduce the risk of cancer and hence support the anti-V-T lobby.  If we're going to get into the nitty-gritty and typically very minor details about, for example, whether the statistical colon-cancer-protective effect of aspirin shows that V-T were wrong, then this really does smell of academic territory defense.

Why do I say that?  Because if we go down that road, we'll have to say that statins are cancer-causing, and so is exercise, and kidney transplants and who knows what else.  They cause cancer by allowing people to live longer, and accumulate more mutational damage to their cells.  And the supposedly serious opioid epidemic among Trump supporters actually is protective, because those people are dying earlier and not getting cancer!

The main point is that mutations are clearly involved in carcinogenesis, cell division life-history is clearly involved in carcinogenesis, environmental mutagens are clearly involved in carcinogenesis, and inherited mutations are clearly contributory to the additional effects of life-history events.  The silly extremism to which the objectors to V-T would take us would be to say that, obviously, if we avoided any interaction whatsoever with our environment, we'd never get cancer.  Of course, we'd all be so demented and immobilized with diverse organ-system failures that we wouldn't realize our good fortune in not getting cancer.

The story and much of the discussion on all sides is also rather naive even about the nature of cancer (and how many or of which mutations etc it takes to get cancer); but that's for another post sometime.

ADDENDUM 2
I'll add another new bit to my post, that I hadn't thought of when I wrote the original.  We have many ways to estimate mutation rates, in nature and in the laboratory.  They include parent-offspring comparison in genomewide sequencing samples, and there have been sperm-to-sperm comparisons.  I'm sure there are many other sets of data (see Michael Lynch in Trends in Genetics 2010 Aug; 26(8): 345–352.  These give a consistent picture and one can say, if one wants to, that the inherent mutation rate is due to identifiable environmental factors, but given the breadth of the data that's not much different than saying that mutations are 'in the air'.  There are even sex-specific differences.

The numerous mutation detection and repair mechanisms, built into genomes, adds to the idea that mutations are part of life, for example that they are not related to modern human lifestyles.  Of course, evolution depends on mutation, so it cannot and never has been reduced to zero--a species that couldn't change doesn't last.  Mutations occur in plants and animals and prokaryotes, in all environments and I believe, generally at rather similar species-specific rates.

If you want to argue that every mutation has an external (environmental) cause rather than an internal molecular one, that is merely saying there's no randomness in life or imperfection in molecular processes.  That is as much a philosophical as an empirical assertion (as perhaps any quantum physicist can tell you!).  The key, as  asserted in the post here, is that for the environmentalists' claim to make sense, to be a mutational cause in the meaningful sense, the force or factor must be systematic and identifiable and tissue-specific, and it must be shown how it gets to the internal tissue in question and not to other tissues on the way in, etc.

Given how difficult it has been to chase down most environmental carcinogenic factors, to which exposure is more than very rare, and that the search has been going on for a very long time, and only a few have been found that are, in themselves, clearly causal (ultraviolet radiation, Human Papilloma Virus, ionizing radiation, the ones mentioned in the post), whatever is left over must be very weak, non tissue-specific, rare, and the like.  Even radiation-induced lung cancer in uranium minors has been challenging to prove (for example, because miners also largely were smokers).

It is not much of a stretch to simply say that even if, in principle, all mutations in our body's lifetime were due to external exposures, and the relevant mutagens could be identified and shown in some convincing way to be specifically carcinogenic in specific tissues, in practice if not ultra-reality, then the aggregate exposures to such mutations are unavoidable and epistemically random with respect to tissue and gene.  That I would say is the essence of the V-T finding.

Quibbling about that aspect of carcinogenesis is for those who have already determined how many angels dance on the head of a pin.

Darwin the Newtonian. Part II. Is life really 'Newtonian'?

In yesterday's post I suggested that Darwin had a Newtonian view of the world, that is, he repeatedly and clearly described the organisms and diversity of life as the product of evolution, due to natural selection viewed as a force, which in an implicit way he likened to gravity.  At the same time, he knew that there was widespread evidence of various kinds for long-term evolutionary stasis, which a prominent geologist has recently called  "Darwin's null hypothesis of evolution," the idea that evolution does not occur if the environment stays the same.

That suggests that a changing environment leads to a changing mix of organisms that live in the environment, including of their genotypes.  It makes evolutionary sense, of course, because environments screen organisms for 'fitness'.  However, its negative--no change in the environment implies no evolution-- doesn't make sense and badly misrepresents what is widely assumed that we know about evolution. Even if we define evolution, as often done in textbooks, as 'change in gene frequencies' such change clearly occurs even in stable environments.  Mutations always arise, and selectively neutral variants, that is, that don't affect the fitness of their bearers, change in frequency by chance alone, not by natural selection, which means that at the genomic level evolution still occurs. It's curious that not only can organisms stay very similar in what seem like static environments, but also can be similar even in changing environments.

The idea of dual environmental-genetic stasis is an inference made from species that seem to stay similar for long time periods in environments that also appear similar--but how similar are they really?

Indeed, there are several problems with the widely if often implicitly assumed 'null hypothesis':

  1.  It is a very narrow assumption of the meaning of 'evolution', implicitly implying that it refers only to functionally important traits or their underlying genotypes. As we will see, there are ways for genetic change (and even trait change) to occur even in static environments, so that an unchanging environment doesn't imply no biological change.
  2.  It implies that 'the environment' actually stays the same, although 'environment' is hard to define.
  3.  It implies a tight essentially one-to-one fit between genotype and adaptive traits, so that in unchanging environments there will not be any functional genomic change.

All of these assumptions are wrong.  In essence, there cannot be 'the', or even 'a' null hypothesis for evolution.   Sexual reproduction, horizontal transfer, and recombination occur even without new sequence mutation.  To ignore that along with assuming a stationary environment, and adopt a null hypothesis that had anything like mathematical or Aristotelian rigor would be to reduce evolution's basis to something like this not-very-profound tautology:  Everything stays the same, if everything stays the same.

So let's look at this a little more closely
From the fossil record, we infer that some species stay the 'same' for eons, sometimes millions of years.  Then they change.  Gould and Eldridge called this 'punctuated equilibrium' and it was taken as a kind of up-dated version of Darwinism--mistakenly, because Darwin recognized it very clearly at least by the 6th edition of his Origin.  And while some aspects of animals and plants can hardly change in appearance for long time periods, close inspection shows that only some aspects of what can be preserved in fossils stays similar; other aspects typically change.  Also, speciation events occur and some descendants of an early form do change in form, even if the older species seems not to change. So we should be very careful even to suggest that environments or species really are not changing.

But mutations certainly occur and that means that even for a set of fossils that look the same, the genomes of the individuals would have varied, at least in non-functional sequence elements.  That itself is 'evolution', and it is misleading to restrict the term only to visible functional change.  But genetic drift is just the tip of the molecular evolution iceberg.  It is now very clear that there are many ways for an organism to produce what appears to be the same trait--and this is true both at the molecular and morphological levels.  That is, even a trait that 'looks' the same can be produced by different genotypes.  I wrote about this long ago in a rather simple vein, calling it phenogenetic drift, and Andreas Wagner in particular has written extensively about it, with sophisticated technical detail, in his book The Origin of Evolutionary Innovation, and this paper.  (The images are of my general paper and Wagner's book given just to break up the monotony of long text! ; he has written a more popular-level book as well called Arrival of the Fittest, which is a very good introduction to these ideas).

Recent exploration, with great detail

A modest statement of principl

Wagner explores this in many ways and among his views is that the ability of organisms to evolve innovative traits is based on the huge number of overlapping, essentially similar ways it can carry out its various functions, which allows mutations to add new function without jeopardizing the current one. Redundancy is protective against environmental changes as well as enabling new traits to arise.

This is in a sense no news at all. It was implicit in the very foundational concept of 'polygenic' control-- the determination of a trait by independent, or semi-independent of many different genes.  The way complex traits are thus constructed was clear to various biologists more than a century ago, even if the specific genes could not be identified (and the nature of a 'gene' was unknown).  A fundamental implication of the idea for our current purposes is that each individual with a given trait value (say, two people with the same height or blood pressure) can have its own underlying multi-locus genotype, which can vary among them.  Genotypes may predict phenotypes, but a phenotype does not accurately predict the underlying genotype (a deep lesson that many who promote simplistic models of causation in biomedical contexts should have learned in school).

And of course that does not even consider environmental effects, even though we know very well that for most characters of interest, normal or pathological, 'genetic' factors account only for a modest fraction of their variation. And, of course, if it's hard to identify contributing genetic variants, it's at least as difficult to identify the complex environmental contributors who make inference of phenotype from genotype so problematic. That is, neither does genotype reliably predict phenotype, nor does phenotype reliably predict genotype and the idea that they do so with 'precision' (to use todays' fashionable branding phrase) is very misleading.

In turn, these considerations imply that even if we accepted the idea of natural selection as a Newtonian deterministic force, it works at the level of the achieved trait, and can ignore (actually, is blinded to) the underlying causal genetic mechanism.  There can be extensive variation within populations in the latter, and change over time.  Just because two individuals now or in the past have a similar trait does not imply they have the same underlying genotype and hence does not imply there's been no 'evolution' even in that stable trait!

In this sense, evolution could be Newtonian, driven by force-like selection, and still not be genetically static.  But there's more.  How can there actually be stasis in a local environment?  If organisms adapt to conditions, then that in itself changes those conditions.  Even within a species, as more and more of its members take on some adaptive response to the environment, they change their own relative fitness by changing the mix of genotypes in their population, and that in turn will affect their predators and prey, their mate selection, and the various ways that the mix of resources are used in the local ecology.  If, say, the members of a species become bigger, or faster, or better at smelling prey, then the distribution of energy and species size must also change.  That is, the 'environment' cannot really remain the same.  That ecosystems are fundamentally dynamic has long been a core aspect of population ecology.

In a nutshell, it must be true that if genotypes change, that changes the local environment because my genotype is part of everybody else's 'environment'. In that sense, only if no mutations are possible can there be no 'evolution'. Even if one wants to argue that all mutations that arise are purged in order to keep the species the 'same', there will still be a dynamic mix of mutational variants over time and place.

One could even assert that an essence of Darwinism, literally interpreted, is that environments cannot be the same because the adaptation of one species affects others, even were new mutations not arising, because it affects the fitness of others. That is what his idea of the relentless struggle for existence among species meant, so stasis did cause him a bit of a problem, which he recognized in the later edition of the Origin.

I think that in essence Darwin viewed natural selection as being basically a deterministic force, like gravity, corresponding to Newton's second law of motion. And the idea of stasis corresponds to Newton's first law, of inertia. Today even many knowledgeable biologists seem to think in that way (for example, invoking drift only as a minor source of 'noise' in otherwise force-like adaptive evolution). Selective explanations are offered routinely as true, and the word 'force' routinely is used to explain how traits got here.
But there are deep problems even if we accept this view as correct.  Among other things, even if natural selection is really force-like, or if genetic drift exists as a moderating factor, then these factors should have some properties that we could test, at least in principle.  But as we'll see next time, it's not at all clear that that is the case.

If mutations can go viral, adaptationism is less annoying.

Feb. 9, 2016: I have edited the paragraph beginning with "Exciting..." to remove details of mutation rates because my initial posting was probably wrong about coding vs. non-coding mutation rates. To fix that requires much more nuance than is relevant for the point I'm making in that paragraph, not to mention much more nuance than I'm capable of grasping immediately! Cheers and thanks to Daniel and Ken in comments below and to everyone who chimed in on Twitter. 

***

I always account for virally-induced mutation when I imagine the evolution of our genome. That's because I'll never forget this quote. Who could?

“Our genome is littered with the rotting carcasses of these little viruses that have made their home in our genome for millions of years.” - David Haussler in 2008 

Or this...

"Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements." (source and see this)

Exciting virus discoveries aside, we're constantly mutating with each new addition to the human lineage. Thanks to whole genome sequencing, the rate of new mutation between human parent and offspring is becoming better known than ever before. We each have new single nucleotide mutations in the stretches of our DNA that are known to be functional (very little of the entire genome) and that are not (the majority of the genome). These are variants not present in our parents’ codes (for example, we might have a ‘T’ where there is a ‘A’ in our mother’s code). And there are also deletions and duplications of strings of letters in the code, sometimes very long ones. Estimates vary on parent-offspring mutation rate and that's because there are different sorts of mutations and individuals vary, even as they age, as to how many mutations they pass along, for example. Still, without any hard numbers (which I've left out purposefully to avoid the mutation rate debate), knowing that there is constant mutation is helpful for imagining how evolution works. And it also helps us understand how mutations even in coding regions aren't necessarily good nor bad. Most mutations in our genome are just riding along in our mutation-tolerant codes—where they will begin and where they will go no one knows!

And it's with that appreciation for constant, unpredictable, but tolerated mutation—of evolution's momentum, of a lineage's perpetual change, selection or not—on top of a general understanding of population genetics that just makes adaptation seem astounding. It makes it difficult to believe that adaptation is as common as the myriad adaptive hypotheses for myriad traits suggest.

That's because this new raw material for adaptation, this perpetual mutation, really is only a tiny fragment of everything that can be passed on. But, what's more, each of those itty bitty changes could be stopped in its tracks before going anywhere.

The good, the bad, and the neutral, they all need luck to pass them onto the next generation. That's right. Even the good mutations have it rough. Even the winners can be losers! Here are the ways a mutation can live or die in you or me:

The Brief or Wondrous Life of Mutations, Wow.

This view of mutation fits into that slow and stately process that Darwin described, despite his imagination chugging away before he had much understanding of genetics.

Of course, bottlenecks or being part small populations would certainly help our rogue underdogs proliferate, and swiftlier so, in future generations.

Still, trying to imagine how any of my mutations, including any that might be adaptive, could become fixed in a population is enough to make me throw Origin of Species across the room.

By "adaptive," I'm talking about "better" or "advantageous" traits and their inherited basis ... that ever-popular take on the classic Darwinian idea of natural selection and competition.

For many with a view of mutation like I spelled out above, it's much easier to conceptualize adaptation as the result of negative selection, stabilizing selection, and tolerant or weak selection than it is to accept stories of full-blown positive selection, which is what "Darwinian" usually describes (whether or not that was Darwin's intention). One little error in one dude's DNA plus deep time goes all the way to fixed in the entire species because those who were lucky enough to inherit the error passed it on more frequently, because they had that error, than anyone passed on the old version of that code? I guess what I'm saying is, it's not entirely satisfying.

But what if a mutation could be less pitiful, less lonely, less vulnerable to immediate extinction? Instead, what if a mutation could arise in many people simultaneously? What if a mutation didn't have to start out as 1/10,000? What if it began as 1,000/10,000?

That would certainly up its chances of increasing in frequency over time, and quickly, relative to the rogue underdog way that I hashed out in the figure above. And that means that if there was a mutation that did increase survival and reproduction relative to the status quo, it would have a better chance to actually take over as an adaptation. This would be aided, especially, if there was non-random mating, like assortative mating, creating a population rife with this beneficial mutation in the geologic blink of an eye.

But how could such a widespread mutation arise? This sounds so heartless to put it like this, but thanks to the Zika virus, it seems to me that viruses could do the trick.

Electron micrograph of Zika virus. (wikipedia)

I'd been trapped in thinking that viruses cause unique mutations in our genomes the way that copy errors do. But why should they? If they infect me and you, they could leave the same signatures in our genomes. And the number of infected/mutated could increase if the virus is transmitted via multiple species (e.g. mosquito and human, like Zika). If scientists figure out that the rampant microcephaly associated with the Zika virus is congenital, wouldn't this be an example* of the kind of large-scale mutation that I'm talking about? 

*albeit a horrifying one, and unlikely to get passed on because of its effects, so it's not adaptive whatsoever.

If viral mutations get into our gametes or into the stem cells of our developing embryos, then we've got germ-line mutation and we could have the same germ-line mutation in the many many genomes of those infected with the virus. As long as we survive the virus, and we reproduce, then we'll have these mutant babies who don't just have their own unique mutations, but they also have these new but shared mutations and the shared new phenotypes associated with them, simultaneously.

Why not? Well, not if there are no viruses that ever work like this.

We need some examples. The mammalian placenta, and its subsequent diversity, is said to have begun virally, but I can't find any writing that assumes anything other than a little snowflake mutation-that-could.

Anything else? Any traits that "make us human"? Any traits that are pegged as convergences but could be due to the mutual hosting of the same virus exacting the same kind of mutation with the same phenotypic result in separate lineages?

I've always had a soft spot for underdogs. And I've always given the one-off mutation concept the benefit of the doubt because I know that my imagination struggles to appreciate deep time. What choice do you have when you think evolutionarily? However, just the possibility that viruses can mutate us at this larger scale, even though I know of no examples, is already bringing me a little bit of hope and peace, and also some much needed patience for adaptationism.

***

Update: I just saw this published today, asking whether microcephaly and other virus-induced birth defects are congenital. Answer = no one knows yet: http://www.nytimes.com/2016/02/09/science/zika-virus-microcephaly-birth-defects-rubella-cytomegalovirus.html?partner=IFTTT&_r=1

Food-Fight Alert!! Is cancer bad luck or environment? Part I: the basic issues

Not long ago Vogelstein and Tomasetti stirred the pot by suggesting that most cancer was due to the bad luck of inherent mutational events in cell duplication, rather than to exposure to environmental agents.  We wrote a pair of posts on this at the time. Of course, we know that many environmental factors, such as ionizing radiation and smoking, contribute causally to cancer because (1) they are known mutagens, and (2) there are dose or exposure relationships with subsequent cancer incidence. However, most known or suspected environmental exposures do not change cancer risk very much or if they do it is difficult to estimate or even prove the effect.  For the purposes of this post we'll simplify things and assume that what transforms normal cells into cancer cells is genetic mutations; though causation isn't always so straightforward, that won't change our basic storyline here.

Vogelstein and Tomasetti upset the environmental epidemiologists' apple cart by using some statistical analysis of cancer risks related, essentially, to the number of cells at risk, their normal time of renewal by cell division, and age (time as correlated with number of cell divisions).  Again simplifying, the number of at-risk actively dividing cells is correlated with the risk of cancer, as a function of age (reflecting time for cell mutational events), and with a couple of major exceptions like smoking, this result did not require including data on exposure to known mutagens.  V and T suggested that the inherently imperfect process of DNA replication in cell division could, in itself, account for the age- and tissue-specific patterns of cancer.  V and T estimated that except for the clear cases like smoking, a large fraction of cancers were not 'environmental' in the primary causal sense, but were just due, as they said, to bad luck: the wrong set of mutations occurring in some line of body cells due to inherent mutation when DNA is copied before cell division, and not detected or corrected by the cell.  Their point was that, excepting some clear-cut environmental risks such as ionizing and ultraviolet radiation and smoking, cancer can't be prevented by life-style changes, because its occurrence is largely due to the inherent mutations arising from imperfect DNA replication.

Boy, did this cause a stink among environmental epidemiologists!  Now one we think undeniable factor in this food fight is that environmental epidemologists and the schools of public health that support them (or, more accurately, that the epidemiologists support with their grants) would be put out of business if their very long, very large, and very expensive studies of environmental risk (and the huge percent of additional overhead that pays the schools' members meal-tickets) were undercut--and not funded and the money went elsewhere.  In a sense of lost pride, which is always a factor in science because it's run by humans, all that epidemiological work would go to waste, to the chagrin of many, if it was based on misunderstanding the basic nature of the mutagenic and hence carcinogenic processes.

So naturally the V and T explanation has been heavily criticized from within the industry.  But they will also raise the point, and it's a valid one, that we clearly are exposed to many different agents and chemicals that are the result of our culture and not inevitable and are known to cause mutations in cell culture, and these certainly must contribute to cancer risk.  The environmentalists naturally want the bulk of causation to be due to such lifestyle factors because (1) they do exist, and (2) they are preventable at least in principle.  They don't in principle object to the reality that inherent mutations do arise and can contribute to cancer risk, but they assert that most cancer is due to bad behavior rather than bad luck and hence we should concentrate on changing our behavior.

Now in response, a paper in Nature ("Substantial contribution of extrinsic risk factors to cancer development," Wu et al.) provides a statistical analysis of cancer data that is a rebuttal to V and T's assertions.  The authors present various arguments to rebut V and T's assertion that most cancer can be attributed to inherent mutation, and argue instead that external factors account for 70 to 90% of risk.  So there!

In fact, these are a variety of technical arguments, and you can judge which seem more persuasive (many blog and other commentaries are also available as this question hits home to important issues--including vested interests).  But nobody can credibly deny that both environment and inherent DNA replication errors are involved.  DNA replication is demonstrably subject to uncorrected mutational change, and that (for example) is what has largely driven evolution--unless epidemiologists want to argue that for all species in history, lifestyle factors were the major mutagens, which is plausible but very hard to prove in any credible sense.  

At the same time, environmental agents do include mutational effects of various sorts and higher doses generally mean more mutations and higher risk.  So the gist of the legitimate argument (besides professional pride or territoriality and preservation of public health's mega-studies) is really the relative importance of environment vs inherent processes.  The territoriality component of this is reminiscent of the angry assertion among geneticists, about 30 years ago, that environmental epidemiologists and their very expensive studies were soaking up all the money so geneticists couldn't get much of it.  That is one reason geneticists were so delighted when cheap genome sequencing and genetic epidemiological studies (like GWAS) came along, promising to solve problems that environmental epidemiology wasn't answering--to show that it's all in the genes (and so that's where the funding should go).  

But back to basic biology 
Cells in each of our tissues have their own life history.  Many or most tissues are comprised of specialized stem cells that divide and one of the daughter cells differentiates into a mature cell of that tissue type.  This is how, for example, the actively secreting or absorbing cells in the gut are produced and replaced during life.  Various circumstances inherent and environmentally derived can affect the rate of such cell division. Stimulating division is not the same as being a direct mutagen, but there is a confounding because more cell division means more inherent mutational accumulation.  That is, an environmental component can increase risk without being a mutagen and the mutation is due to inherent DNA replication error.  Cell division rates among our different tissues vary quite a lot, as some tissues are continually renewing during life, others less so, some renew under specific circumstances (e.g., pregnancy or hormonal cycles), and so on.

As we age, cell divisions slow down, also in patterned ways.  So mutations will accumulate more slowly and they may be less likely to cause an affected cell to divide rapidly.  After menopause, breast cells slow or stop dividing.  Other cells, as in the gut or other organs, may still divide, but less often.  Since mutation, whether caused by bad luck or by mutagenic agents, affects cells when they divide and copy their DNA, mutation rates and hence cancer rates often slow with advancing age.  So the rate of cancer incidence is age-specific as well as related to the size of organs and lifestyle stimulates to growth or mutation.  These are at least a general characteristics of cancer epidemiology.

It would be very surprising if there were no age-related aspect to cancer (as there is with most degenerative disease).  The absolute risk might diminish with lower exposure to environmental mutagens or mitogens, but the replicability and international consistency of basic patterns suggests inherent cytological etiology.  It does not, of course, in any sense rule out environmental factors working in concert with normal tissue activity, so that as noted above it's not easy to isolate environment from inherent causes.

Wu et al.'s analysis makes many assumptions, the data (on exposures and cell-counts) are suspect in many ways, and it is difficult to accept that any particular analysis is definitive.  And in any case, since both types of causation are clearly at work, where is the importance of the particular percentages of risk due to each?  Clearly strong avoidable risks should be avoided, but clearly we should not chase down every miniscule risk or complex unavoidable lifestyle aspect, when we know inherent mutations arise and we have a lot of important diseases to try to understand better, not just cancer.

Given this, and without discussing the fine points of the statistical arguments, the obvious bottom line that both camps agree on is that both inherent and environmental mutagenic factors contribute to cancer risk. However, having summarized these points generally, we would like to make a more subtle point about this, that in a sense shows how senseless the argument is (except for the money that's at stake). As we've noted before, if you take into account the age-dependency of risk of diseases of this sort, and the competing causes that are there to take us away, both sides in this food fight come away with egg on their face.  We'll explain what we mean, tomorrow.

Imagine no mutation.

Imagine no mutation.
I wonder if you can.
No means for new variation.
A creationist's view of Man.
Imagine all the people
learning it this way.

Boo-hoo, ewww.

I found out this semester that although most of my students in "Human Origins" had learned about natural selection, that relatively few of them had learned about mutation. 

Huh? Are people still stuck on Darwin? Apparently. 

Mutation requires a little bit of genetics to understand, but c'mon! Natural selection makes no sense without it. None.

And what's more, natural selection cannot be the all-powerful force that popular culture might have us believe when mutation is accounted for. Evolution is so much more fascinating with even a basic understanding of mutation. In this molecular-clock, whole-genome-sequencing era, how can anyone teaching and learning evolution not have at least a basic understanding of chance, perpetual accumulation of mutations?

We've all, each and every one of us, got many de novo mutations. So our genomes are distinct from our parents' and siblings', not just because of genetic recombination of our grandparents' genomes when our parents' eggs and sperms were built, but because of unique mutations that occurred while making those germ cells or in the early stages after their union.

That this constant change in lineages is occurring with each reproductive event is proof that natural selection is a largely tolerant process, perpetually allowing perpetual evolution by mutation.

(And, maybe natural selection has much less, and mutation has much more, to do with speciation than many have assumed.)

What happens to each and every one of our unique mutations, whether or not they live on in our offspring, whether or not they play a role in adaptation, depends on quite a bit of luck, partly because of the "Law of Segregation":

A Mutation's Future
Click to enlarge. Email me for original file that you can modify: holly_dunsworth@uri.edu

For a description of evolution that incorporates perpetual mutation, check out "Evolution is the only natural explanation. And it's all we need."

Luck of the draw: Evolving flipbooks mimic non-selective processes (a classroom activity)

First the lesson plan, then a look at the peer-review process that provided feedback.

A common ancestor (center) and its descendants.

Introduction and scope

Even if evolution is accepted and natural selection is understood, learners of all ages may mistakenly explain all variation with this single mechanism. That there are myriad resources for, and examples of, natural selection and because it is so powerful, it is not surprising that the concept is dominant even though selection is not the only means by which evolution occurs. Here I suggest that there should be better coverage of non-selective processes at the introductory level of learning evolution. Towards that goal, I offer an engaging activity involving the drawing of flipbooks, which not only marries art and science but symbolically demonstrates evolutionary mechanisms other than selection.

Leads into—biology, genetics, evolution, the art of animating with flipbooks.

Concepts—Mutation, genetic drift, natural selection, common ancestry, diverging lineages, speciation, inheritance, species identification, developmental constraints, complexity, evolutionary progress.

Target age group—All students who are being introduced to the fundamentals of evolution can perform this simple activity and can learn from it. As long as they can trace a line, they can participate. In schools, evolutionary concepts are formally introduced as early as the sixth grade, but basic concepts like change over time, deep time, and common ancestry may be introduced even earlier. Often students are not formally or rigorously introduced to evolution until they reach college or university. Furthermore, many of the more advanced concepts that can be addressed with this activity are only appropriate for secondary and post-secondary courses. It is up to teachers to decide how to integrate this activity into their evolution lessons. I developed this activity, and used it with success, in my introductory biological anthropology course at the University of Rhode Island.

The importance of teaching beyond selection at the introductory level

Natural selection does not explain all of evolution

             Since Darwin’s time we’ve learned that natural selection is just one mechanism of evolution that works in concert with others such as mutation, gene flow, and genetic drift. Mutation, the result of chance, creates the necessary variation for natural selection and drift to take place. Each human inherits an estimated average of 150 mutated nucleotides per person (Ken Weiss, Pennsylvania State University, personal communication[A]). Like mutation, drift is also random, but drift occurs over time as random events accumulate. Because both are due to differential reproduction, the result of drift can look remarkably like that of selection and change away from the ancestral state can occur quickly if the population size is small (1). A classic example of drift occurs in a small culturally isolated population of the Old Order Amish in eastern Pennsylvania; hardly anyone would hypothesize that the relatively high frequency of polydactyly was due to natural selection. For many traits that seem to have no adaptive value, drift is a strong hypothesis. Often drift is considered alongside relaxed selection (2). That is, a trait becomes prevalent through drift in the absence of selective pressures that would otherwise prevent the drift from occurring. The deterioration of human eyesight may be explained this way and so may geographic variation in earwax (3). Many diagnostic characteristics of the Neanderthal face may be explained by drift (4) and so might the fixed loss of tails in our hominoid ancestry.[B]

           

A strict selection perspective creates potential for societal harm

Learning about evolution solely through natural selection is not only inaccurate but may also have negative social consequences.  Wearing adaptation-colored glasses fosters notions that evolution is progressive, that past states were inferior to present ones, and that there is some striving in nature towards perfection (5, 6). From this perspective it is all too easy to assign differential value, worth, or beauty to variation within and between species under the backing assumption that “Mother Nature” has “favored” one trait over another. Judgments like this can lead to human exceptionalism and anti-environmentalism (justifying human superiority over other organisms) or tribal exceptionalism and racism (justifying superiority of some nose shapes or skin colors over others).[C] Presenting a more complete picture of evolution to those in the early phases of learning about it may lower the risk that these dangerous ideological paths will be followed (7).

Flipbooks for teaching evolution

            Seeds, jelly beans, and the like are common stand-ins for alleles or gametes in classroom exercises meant to recreate evolving populations. These exercises demonstrate how new gene pools result from mutation followed by selection or the lack thereof (i.e. drift).  However, these activities are not appropriate for all ages because of the algebra they require for calculating allele frequencies; even at the university level, students can struggle with the math. Furthermore, these engaging hands-on activities do not allow students to witness more than a few generations of evolutionary change. Alternate illustrations of the effects of mutation and genetic drift on evolution are needed. Recently, Gillings (8) provided a pedagogically useful metaphor of these biological processes with language evolution.

Here I offer another sort of instructional device inspired by two films that were recently posted by artist Clement Valla on the Internet. The films show how line drawings, when traced 500 times, can evolve dramatically. And although it is so simple, this is a powerful demonstration of evolution without natural selection.

***

Teacher Resources

Films by Clement Valla (2010)—Inspiration for this flipbook activity

• “A sequence of lines traced by 500 individuals” Also posted here.
• “A sequence of circles traced by 500 individuals” Also posted here.

On-line resources for the art of flipbook animation

• Wired’s How-To “Make a flip book animation”
• National Gallery of Art, Kids. “On the Move”
• “Escape” (flipbook animation)
• “Flip Mania Part 1: Sports” (flipbook animation)
• “Simpsons Fight” (flipbook animation)

On-line resources for teaching and learning about the role of chance in evolution

General evolution:

• NOVA’s “Evolution”
• Berkeley’s “Understanding Evolution for Teachers”

Genetic drift:

• University of Arizona’s “The Biology Project”
• University of Connecticut’s genetic drift simulator

Mutation:

• University of Utah’s “Learn.Genetics”
• NIH’s “Genetics Home Reference”

Misconceptions about evolution:

• AAAS Science Assessment. Topics: Evolution and natural selection
• New Scientist’s “Evolution: 24 myths and misconceptions”

***

Valla’s films are basically digital renderings of classic flipbooks used by cartoon animators and by following the steps in the activity outlined below, teachers can easily recreate the experience of the films with students in the classroom. In addition, they can use this exercise to teach an array of evolutionary principles and concepts.

If learners can trace lines they can perform this activity. As a collaborative endeavor, this activity works with a minimum of two participants and, theoretically, has no maximum group size. With 50 tracings per book, it takes about 50 minutes to complete.[D] At the end, students will have created flipbook animations that “evolved” merely because each of their tracings, no matter how diligently drawn, was slightly different from the previous one.

Materials

·       One pencil or pen for each participant

·       Two blank flipbooks for each participant. There are several ways to fashion flipbooks. They can be small blank notebooks with at least 50 plain white sheets that are slightly transparent for tracing purposes. A much cheaper method is to fasten sheets of copier paper together with a binder clip. The paper should be cut down with a paper cutter to pages with roughly 3 inches (or 8 cm) on each side and not too much larger than that because large books beg for large drawings that slow down the activity. To get seamless animation while flipping through the flipbook, the flipping edges of the pages need to be lined-up, so tap the stack of pages on a table top to settle them all together on one edge before clipping them together and beginning the drawings.  Once the flipbook drawings are underway, the clip cannot be moved or removed.

Procedures

1.     Set the stage. Prior to performing this activity, provide students with background information  on flipbook animation and on concepts of common ancestry, the Tree of Life, evolution, and mechanisms of evolution (natural selection, mutation, and genetic drift). 

***

Questions to gauge knowledge and spark interest before the activity

Teachers will need to choose the questions that are appropriate for their students’ learning level and for the particular evolutionary lessons they want to address.         

Change through time and common descent—What is evolution? What is the evidence for it? How does it occur? What is the concept of common ancestry that is used to build the Tree of Life?

Evolutionary mechanisms—What is natural selection? What are other ways that evolution occurs besides natural selection? What is genetic drift and how is it different from and similar to natural selection? What is a mutation? What causes mutations? How frequent are mutations? What keeps mutations from happening more frequently than they do? Are mutations always bad? How could something that starts as a mutation in an individual end up in more and more individuals in a population over generations and through time?

The nature of evolution—Is evolution progressive? Is there a goal? Does it always result in improvement over earlier forms?

***

2.     Draw the templates.

a.      Have students put their names on the front covers of their books.

b.     Have them open one of their flipbooks to the last page and draw something. Keep it a simple line drawing so that it does not take longer than 10 seconds to trace. The drawing can be an unknown shape, like a doodle or scribble (known here as “unrecognizable”; Figures 1-4). Or the drawing can be a symbol like a number or letter, an amoeba or Mona Lisa (known here as “recognizable”; Figures 5-8). It is important that both types of templates are represented because the “recognizable” templates may experience stabilizing natural selection. That is, tracers of familiar shapes may have stronger expectations about how their tracing should appear. If they have such expectations, they may trace with fewer mistakes and/or correct the mistakes that previous tracers have made. But the “unrecognizable” templates may experience less, if any, of this conservative influence. Do not explain the rationale to the students yet because it will be part of the discussion after the completion of the exercise. The bottom line is that teachers make sure that both unrecognizable and recognizable templates are created. They may also want to encourage some students to draw creatures (see explanation in “concluding remarks”).  

c.      Optional modification: I had several students use identical templates—rather than having each student draw a unique one—so that they could witness several different lineages, not just two, evolving from a common ancestor (Figures 1-8). The only downside to this modification is that students are not given the opportunity to create their own templates. Also, teachers may wish to copy and cut out the templates from Figures 1-8 and glue them in the flipbooks before handing them out to students. This would allow students to compare their results (i.e. descendants) with the ones published here.

d.     Have the students carefully trace their template into their second book. Each of them will now have two flipbooks with identical templates. They may rotate the tracing so that the second template is oriented differently in the book.

3.     Introduce the activity. Briefly describe Step 6—that they’re about to pass the books around and each of them will trace the tracing of the person who went before them until the books are filled up. The result will be flipbooks that contain animated movies of the tracings beginning with the original templates.  

4.     Make predictions. Ask the students: What will your book’s animation be like? What will the last picture in your book look like? Will your two books’ animations be identical? What does the template symbolize in evolutionary terms? What do your two flipbook animations symbolize?

5.     Establish the rules

·       Trace as best as you can, but in a brief amount of time.

·       Joking is fine, but do not give anyone grief for “messing up” a flipbook with their mistakes. Everyone’s tracings are imperfect copies. 

·       You may only look at the page that you are tracing. You may not flip back and look at any previous drawings in the book that build up as this activity goes along.

·       You must pass the book to the next tracer in a way that keeps it open to your drawing (i.e. the drawing that the next person will trace).

6.     Trace in an assembly line to build the flipbooks.

1. Each student will turn one page down over the template and trace it and then pass the book to the right.
2. Each tracing should take a few seconds and, ideally, everyone should take roughly the same amount of time.
3. Trace, pass, trace, pass, and repeat to fill all pages of the book.

7.     Observe, discuss, and explain the evolving animations. When filled-up, make sure each flipbook makes its way back to its owner. Each student will have two flipbook animations of the evolution of their template drawing, starting with the template and ending with the last tracing. Now they are ready to explain the evolution that occurs in their books.

Results

Figures 1-4. “Unrecognizable” template (i.e. ancestor; center circle) and the resulting drawings (i.e. descendents) after 50 tracings carried out in different flipbooks (i.e. divergent evolutionary paths).

Figures 5-8. “Recognizable” template (i.e. ancestor; center circle) and the resulting drawings (i.e. descendents) after 50 tracings carried out in different flipbooks (i.e. divergent evolutionary paths).

***

Questions to gauge understanding and to spark further study after the activity

Teachers will need to choose the questions that are appropriate for their students’ learning level and for the particular evolutionary lessons they want to address. 

Results—What happened to the templates? Were your predictions correct? Were there differences in the outcomes of the identical templates? Describe the differences in size and shape (morphology) between your template and your final drawings: What were the trends, if any, through time? Did any new traits appear? Did any old traits disappear?  Look around at the other flipbooks and distinguish “recognizable” from “unrecognizable” templates (as described in Step 2b):  Were there any differences in the outcomes of their evolution?

Evolutionary mechanisms—How can you explain what happened to your drawings? What caused the evolution in your flipbooks? Explain the evolutionary history of the last drawing in each of your flipbooks.

Speciation and species concepts—Are the final drawings in your two flipbooks different species from your template (i.e. their common ancestor)? Are the two final drawings different species from each other? Can you identify the moment (i.e. the particular tracing) when a new species originated?

Luck, chance, randomness, and non-random constraints—What does luck, chance and randomness have to do with evolution? Is natural selection random? Look at the differences and similarities between any two neighboring pages in a flipbook. Are there many major differences between the two tracings? What does this suggest about phylogenetic and developmental constraints in evolution? Is evolution predictable? Are there any hypothetical evolutionary changes to an organism, like Homo sapiens, that are implausible or highly unlikely?

Scales of variation and modes of inheritance—Are your animations symbolic of the evolution of a strand of DNA, a protein, a cell, a single-celled organism, a tissue, an organ, a multicellular organism, or a population? Are your animations depicting the results of asexual or sexual reproduction through time? What are the differences for each, in terms of how variation gets into the next generation?

Explaining human evolution—List hypotheses for the evolution of variation in human nose shape. Point out which hypothesis most closely mimics the process in your flip book animation. Describe, in as much detail as possible, how the different hypotheses could be tested. Include materials and methods. Then discuss any problems that you can anticipate with confidently supporting one hypothesis over another and suggest some possible workarounds or solutions to those problems.

Complexity, progress, and perfection—Would you describe your final drawings as more complex than your template? What about the reverse? Would you say that your animations depict progress? Progress and perfection are valued in our society, so what’s the trouble with perceiving human evolution to be progressive, or to be striving towards perfection or some ideal form?

***

  

Concluding remarks

            This activity illustrates the impact of luck on evolution—when chance is a factor (mutation and drift) and when it is not (natural selection). Students may also use the flipbooks to learn the principles of common ancestry, divergent evolution, and speciation. More advanced students can explore concepts of inheritance, species identification, developmental constraints, complexity, and evolutionary progress.

Over the course of three trials of this activity, I found that there were observable degrees of evolutionary change in all flipbooks, whether they had unrecognizable or recognizable templates (Figs. 1-8). Even if there seemed to be conservative influences on the recognizable templates as predicted in Step 2b, evolution still occurred simply because human tracers are not perfect. The various degrees of distance between template and results (e.g. Figure 5) nicely demonstrate the various speeds of evolutionary change, with some organisms retaining more ancestral traits than others.

There was another sort of issue with the recognizable templates, specifically the ones that represented creatures. Some of my students who had these templates (Figures 7 & 8) were the only students to ignore chance and instead describe their animations with natural selection. For example one student explained that, “What started as a lizard evolved to a blob maybe because it could survive better without legs.” Another wrote, “Natural selection may have occurred in my animation because of environmental changes that caused the need for certain features on the body.”  These answers reveal common misunderstandings of natural selection (which are due in no small part to our pedagogical language: 9), but they also illuminate a deeper struggle with accepting and identifying randomness in evolutionary scenarios. Because this activity is designed to help overcome these issues, I recommend that teachers encourage some students to draw templates of creatures so that these fundamental problems, if present, are more likely to surface.

Although natural selection is not responsible for the evolution in the flipbook animations, teachers should not forget to discuss how natural selection is involved in this activity: it is the non-random process behind our cells’ ability to copy DNA without making many mistakes and it is mimicked by tracing in the flipbooks. However, like tracing drawings, DNA replication is imperfect and the chance variations that arise are a fundamental component of evolution.

With these flipbooks students can see for themselves, albeit in a symbolic way, how random mutations can contribute to complexity by flipping through the “recognizable” flipbooks backwards (from the last tracing to the template). When viewed in reverse, the animations evolve from (perceived) simplicity to (perceived) complexity. And when students are reminded that all the mistakes in the tracings (i.e. the mutations) are still the same and that it’s just the sequence of these mistakes that differs in the reverse view, a dialogue is opened up about the roles of chance and deep time in the evolution of complex life (10).  Students can reflect on whether chance mutations and drift could have produced a flipbook that started with a blob and ended with a symbol. After gaining this insight, they are better poised to question the relevance of probability-based arguments against evolution and the origin of life (11). 

The roles of luck, chance and randomness too often take a back seat to natural selection and this activity is meant to help introductory students achieve a more complete view of evolution from the start. Although I cannot guarantee that every student will be evolutionarily enlightened or artistically inspired by this activity, it will provide teachers and students with tools for overcoming some of the mistaken assumptions about evolution that we so often inherit and propagate.

Acknowledgments

            Thanks to B. Bailey, N. Bailey, A. Collado, J. Conrad (and the lizard), W. Harcourt-Smith, G. Felda, C. Mesyef, D. Nelson, B. Shearer as well as the students in my two sections of ‘APG 201: Human Origins’ at The University of Rhode Island during the Fall 2011 semester for providing valuable input during the development process.  Thanks also to Anne Buchanan, Norman Johnson, Kevin Stacey, and Ken Weiss for their most helpful comments on the manuscript. Clement Valla’s art was the spark and I’m grateful for it.

References

1.      Helgason A,  et al. (2009) Sequences from first settlers reveal rapid evolution in Icelandic mtDNA pool. PLoS Genet 5(1): e1000343. doi:10.1371/journal.pgen.1000343

2.      Lahti DC, Johnson NA, Ajie BC, Otto SP, Hendry AP, Blumstein DT, Coss RC, Donohue K, Foster SA (2009) Relaxed selection in the wild. Trends in Ecology and Evolution 24: 487-496.

3.      Yoshiura K, et al (2006) A SNP in the ABCC11 gene is the determinant of human earwax type. Nature Genetics 38: 324-330.

4.      Weaver TD, Roseman CC, Stringer CB (2007) Were neandertal and modern human cranial differences produced by natural selection or genetic drift? J Hum Evol 53: 135-145.

5.      Gould SJ, Lewontin RC (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc R Soc Lond B 205: 581-598.

6.      Weiss KM, Dunsworth HM (2011) Dr. Pangloss’s nose: In evolution, cause, correlation, and effect are not always identical. Evolutionary Anthropology 20:3-8. 

7.      Johnson NA, Lahti DC, Blumstein DT (in press) Combating the assumption of evolutionary progress: Lessons from the decay and loss of traits. Evolution: Education and Outreach.

8.      Gillings MR (in press) How evolution generates complexity without design: Language as an instructional metaphor. Evolution.

9.      Nehm RH, Rector M, Ha M (2010) "Force Talk" in evolutionary explanation: Metaphors and misconceptions.  Evo Edu Outreach 3:605–613.

10.   Nilsson DE, Pelger S (1994) A pessimistic estimate of the time required for an eye to evolve. Proc R Soc Lond B 256: 53-58.

11.   Morris HM (2003) The mathematical impossibility of evolution. Back to Genesis, 179. El Cajon, CA: Institute for Creation Research. Available via the Internet. Accessed 2011 December 22.

---

[A] Estimated roughly with the equation 2.5 x 10^-8 mutations per generation, per 6 billion nucleotides based on published rates (e.g. Pelak et al., 2010.PLoS Genetics 6(9): e1001111).

[B] I cannot find a reference containing this hypothesis, but I cannot find one containing a selection-based hypothesis for ape tail loss either.

[C] For just one example of a scholarly treatment of these issues see ‘Race’ is a Four-Letter Word by C. Loring Brace (Oxford University Press, 2005).

[D] This estimate is based on three trials with ten, 25 and 30 students, respectively. However, making 50 tracings takes just as long with 25 students as it does with 125 students. This time estimate of 50 minutes only includes time for instruction and drawing. It does not include the time spent priming the students on evolutionary concepts and discussing the results. For my students, those discussions continued for the rest of the semester because the flipbooks were a useful touchstone for new concepts down the line. 

Behind the article 

It’s tough to get a paper accepted for publication. This one was rejected from an education series in a scientific journal. I chose to submit there because it's open access (and was prepared to pay if the fee wasn't waived) and the series is billed as a forum for classroom activities, not education research. 

I consider the three reviews (below) to be pretty supportive, especially #2, and think that with just a few revisions I could ameliorate the first reviewers' concerns about citing more literature.

But the academic editor’s concerns about assessment, as outlined in the cover letter (also below), which also echo #3's concerns about Intelligent Design (ID) would require much more work to address. Those issues, along with the extremely low-tech methods (just my hunch), is why I think that they rejected my paper rather than ask me to revise it.

Clearly a lot of my article's shortcomings stem from the fact that I am a college professor and not a trained primary-secondary school teacher, who must meet particular standards of evaluation and assessment. I might also have a poor understanding of the minds of students who are learning biology in high school (or younger). My attempt to transcend those things and address common difficulties that we all share with understanding and teaching evolution... at all levels of learning... well, it failed to be seen as that... perhaps because I failed at doing that! 

I chose not to submit elsewhere because I don’t know of many other open access journals that publish lesson plans and, from my personal perspective, I don't see the point of publishing a lesson plan if it’s not open access. I bet you’re thinking that tenure’s the point. Well, if my choices are (a) submit somewhere else and risk burying it in a journal that few will see, or (b) turn my focus to other publications for my tenure portfolio and make this activity available, now, to anyone with Internet access who visits us here on the Mermaid’s Tale...

...then, I’ll take b.

I'm posting the letter and reviewer comments (with my comments in italic red) for a few reasons: (1) if you decide to try this activity, the comments will help you anticipate any issues or problems you may have; (2) you can see the kind of reviews that a paper like this gets and the sorts of things that people require of evolution lesson plans; (3) it's in the spirit of open access which is what this manuscript has been about from the start of my writing it. 

Article submitted on December 28, 2011, Reviews back on February 10, 2012 

So swiftly returned!

Dear Dr. Dunsworth,

Thank you very much for submitting your manuscript "Luck of the draw: Evolving flipbooks mimic non-selective processes" for review by _________. As with all papers reviewed by the journal, yours was assessed and discussed by the editors. In this case, your article was also assessed by an academic editor with relevant expertise and three independent reviewers. Based on the reviews, I regret that we will not be able to accept this manuscript for publication in the journal.

The reviews are attached, and we hope they may help you should you decide to revise the manuscript for submission elsewhere. I am sorry that we cannot be more positive on this occasion.

Overall, the reviewers and the academic editor thought the approach is innovative, though should be more firmly grounded in the prior work dealing with students' understanding of "random" and evolutionary processes.

I honestly thought it was grounded in common knowledge, but I should have cited this and this. (A useful side tip: I perform pre- and post-tests at the beginning and end of each semester with a survey that I built thanks to Cunningham and Wescott's paper. The survey really helps me gauge where students are and where they end up so that each semester I can hopefully help them end up even better. This semester I showed them last semester's stats on day one, tackling some of the issues head-on, like the fact that before taking my course 8% of them think dinosaurs and humans lived at the same time in the past, and 84% think that new traits arise because they need to.)

In addition, the academic editor worried that the activity runs the risk of confusing students by omitting a big piece of the process (selection).  

I assumed that selection would be covered well in other ways and that this activity would complement those efforts.

The reviewers also point out that it is unclear how the activity could be evaluated so that others could determine its efficacy relative to other activities.

If this is how teachers operate, then I’ve got a lot to learn. I didn't have a control group either. Never do!

The evaluation suggestions will be difficult to access, since many rely upon how "different" two drawings are, something that will be difficult to measure accurately and consistently.

It's hard not to jump to this conclusion: If you can’t assess the students’ work easily, then don’t have them do those things or think about those things. Alternatively, it could mean that to publish a lesson plan you must provide teachers with ways to assess the all the things that they ask of their students. Maybe this is one of the big differences between college and everything that comes before it.

For example, because individual viewers may well have different views as to whether or not the flip animations differ from the template, an exercise controlling for or illustrating the bias in viewer perspectives would seem necessary.

This is an exercise that illustrates the subjectivity. I think the issue here is that I should have included explicit instructions for counting, measuring or otherwise evaluating traits and their changes over time, and in deciding whether different drawings should be called separate species or not, rather than suggesting that teachers merely ask students to do all that on their own. But to me setting students free to do those things is a pretty important, and effective, part of the process assuming that the fundamental concepts will be covered in class as follow-up (something I assume teachers would do if speciation and classification were topics that they chose to address with the flipbooks). I think this is, again, my limited experience and college-level bias showing.

Even more problematic, however, is the possibility that students might take away the message that rather than random processes, overlaid by selection, account for increasing complexity in evolution, it is the work of an "intelligent designer." This is obviously not your intent, but something that Reviewer 3 points out may occur.

I had a hunch I’d get pinned for unintentionally promoting ID and I thought I was anticipating some of that in my concluding remarks. If teachers take on those issues (and I hope they do!) there are myriad resources out there to support them starting here and here on the MT and also here: http://ncse.com/.

I hope you appreciate the reasons for this decision and will consider _________ for other submissions in the future. The support of the community is essential if open access publishing is going to succeed, so thanks again for your interest.

Sincerely,
Editor
------------------------------------------------------------------------
Reviewer Notes:

Reviewer #1: While the author has identified a challenging educational issue - differentiating drift and selection as mechanisms of evolution - I found the framing of the problems and the connections to the instructional activity tenuous. There is an extensive literature dealing with students conceptions of "random" event, evolution, and teleological reasoning, none of which were referenced here. The activity was clearly described and sufficient context was supplied to support a teacher interested in adopting it for classroom use. There was, however, no evidence that the activity support the intended learning outcomes or that students enjoyed the lesson. I think we need to have a wide range of strategies for engaging students in evolutionary reasoning and in certain situations this resource may provide a mechanism for raising students awareness about the potential role of drift in evolutionary change. Unfortunately, I don't think this manuscript fits well in this journal and I believe it would be strengthened by connecting it to existing educational research.

Reviewer #2: The paper Luck of the Draw: Evolving flipbooks mimic non-selective processes describes an activity where students create flipbooks by tracing over drawings of either recognizable or unrecognizable templates.  Because tracing is not perfect, and students repeat the tracing effort over many pages, the final outcome provides an example of how small random changes can lead to evolution.  The paper is extremely well written, and the idea of the flipbooks very creative.  The author provides exceptional resources, including links to teaching tools explaining the art of animation, to leading questions for student follow-up and assessment of understanding.  The added figures help the reader visualize the degree of variation that can accumulate over the course of the exercise.  The focus on helping students understand how random events influence evolution is great.  The author correctly identifies a significant problem - too many activities focus on selection, and students, who are already challenged in understanding the concept of random, all too often believe evolution equals natural selection.  Many of the antievolution arguments focus on the perceived impossibility of random events resulting in the evolution of complex structures.  Helping students understand how random events might influence evolutionary change is a very worthwhile educational strategy.

Reviewer #3: This is a very good foundational activity for introducing evolutionary mechanisms.  The chief concern relates to the directionality and complexity issues raised in the concluding remarks, which may be an unavoidable result of the tracing instructions given to students. It seems as though attempts to trace will always result in degradation of initial templates into blobs, which feeds into the 2nd law and mathematical impossibility notions advanced by creationists. So while you may be able to introduce other mechanisms, is one doing so at the risk of demonstrating that the "intelligent designer" of the student themselves is really the take away lesson.  While the point of this exercise may be to raise awareness of the random aspects of evolutionary processes, it may not be clear to students (or pre-college teachers), that they should expect this sort of behavior from such a random process, and that the accumulation of order and complexity results from the overlaying of selection onto random variation.  One suggestion to be considered is to ask if it might be possible to give the students any other instruction that could lead to an accumulation of complexity, without being too Panglossian or feeding into even worse ID notions. Maybe something like "if you see an acute angle, make it into a loop", or something similar that might lead to feature accumulation without having students try to achieve a predetermined target shape. The concern still is that the reason for the variation to be introduced is being produced by the generator, not the system. For more advanced student audiences it seems appropriate to suggest that teachers provide some refutation of the mathematical impossibility argument based on the idea that specifying any specific outcome for a probabilistic system is difficult, but that some outcome has to result.

Part of what  this reviewer is picking up on with the flipbook metaphor/activity is that tracing errors seem to miss parts more than add parts. This would appear to play into Behe's and other ID/creationist arguments that  mutations only chip away at complexity rather than contribute to it. Obviously this activity is only a metaphor and it also cannot go without a companion lesson in selection (which helps a great deal with complexity). One way to avoid giving the impression that mutations only take away complexity would be to stick to unrecognizable templates. But I don't recommend doing that since the recognizables offer great opportunities for teaching the important random mechanisms that are the focus of the lesson. (See 'concluding remarks' where I explain how the recognizables are where students struggle to see the role of chance.) I think that I inadvertently encouraged this reviewer's concern with my wording in that second to last paragraph in the 'concluding remarks.' I should have pointed out how some resulting drawings appear more complex than the templates before going into the trouble with perceiving complexity in the recognizable ones. I think I underestimated how powerful this metaphor could be.


But, overall, regarding #3's issues... I am satisfied with what I laid out in my concluding remarks. Teachers may choose to face the complexity issue explicitly in class and if so they should probably discuss how mutations that cause variation do contribute to the evolution of complexity--even with a mutation that reduced the number of chromosomes in the human lineage, we consider ourselves more complex than chimpanzees who retained one more pair than we did. In the article I cited the famous eye evolution paper for demonstrating the evolution of complexity over time with the accumulation of small mutations. You could also discuss gene duplication's role in complexity. You could talk about hox gene expression in bat wings and bird beaks. You could discuss lactase enzyme production into adulthood and the various known SNPs to allow this in some populations. Even the famous sickle-cell and malaria example illustrates how mutations add to complexity. Ken and Anne have recently listed off a few examples here. Some of these issues raised by ID and anti-evolution folks aren't much more than semantic arguments and differences of perspective...which are issues that stray far from the real biological ones they claim to be about. The same is true, I suspect, for some debates within the evolutionary sciences.


Regarding the suggestion to ask students to deliberately change the drawings in directed ways... I'm uncomfortable with changing the human tracer away from what it is--an imperfect DNA copier--because I worry that would support notions of agency, religious and secular alike! (see my rant here) I also don't think that it's up to an evolution lesson to disprove agency because nobody can do that. What we can do is show how evolution occurs without agency (like we do with this activity). 
------------------------------------------------------------------------

My final thoughts and requests for teachers

These reviews have left me feeling a bit daunted about helping to strengthen evolution education at its earlier stages so that fewer people make it to college and through college so full of misconceptions. If the pre-college rule is that you can't teach something that can't easily be assessed or that you can't teach something that would possibly be fodder for creationists, then I think we risk miring ourselves in the status quo. Religious objections are only one  kind of obstacle to learning and teaching evolution, and letting that one obstacle dominate our pedagogy limits our ability to overcome the rest of them.

Teachers, if you try 'Luck of the draw' please consider the issues raised by the people who put time and effort into reviewing it. 

Take my word for it--students have a lot of fun with it and learn a lot from it. It's a great activity to have students perform if you're away traveling. They can meet somewhere more exciting than the classroom, trace the books together, then bring them back to the next class for discussion when you return.

Trust me, it's not complicated--it's just that there are so many concepts you can choose to run with!

And when you're all done, please leave feedback here. I'd love to know how it goes! I'd love to hear suggestions for improvement!

(c) Holly Dunsworth
Note: I know it's a blog, but this is where I chose to publish. That means, if you use this then find a way to cite it, please. Thanks and welcome to the future!


I'll gladly share a nice printer friendly version of 'Luck of the draw' with anyone who'd like it. Just let me know.